Coronary arteriosclerosis is known to precede and be the major cause of the onset of various pathological conditions such as angina pectoris and myocardial infarction. Luminal narrowing caused by arteriosclerosis and loss of vascular elasticity bring about deficiency of nutrition and oxygen in cardiac muscular tissue, to thereby induce the aforementioned pathological conditions. Narrowing of vascular lumina is considered to be primarily caused by accumulation of foamy macrophages and cholesterol on the inner wall, and in addition, by cell-fibrous intimal hypertrophy caused by migration of smooth muscle cells of the media into the intima, and proliferation of the cells in the intima. In the treatment of angina pectoris and myocardial infarction, antithrombotic agents, vasodilator agents, etc. have been used for the principal purpose of ameliorating the symptoms. However, these agents have failed to serve as a radical remedy for the narrowing and loss of elasticity of vascular lumina caused by arteriosclerosis. Therefore, pharmaceuticals that are capable of preventing or treating intimal hypertrophy which causes angiostenosis are earnestly desired.
In recent years, angiostenosis has been surgically treated by percutaneous transluminal coronary angioplasty (hereinafter referred to as PTCA). PTCA is a therapy in which a balloon catheter is inserted by remote operation into the narrow segment through, for example, the femoral artery, without performance of thoracotomy, and the balloon is inflated in situ, to thereby physically achieve vasodilation. Due to advancement in manipulation technique of PTCA, more than 90% of PTCA cases show amelioration of symptoms immediately after PTCA. In addition, PTCA rarely involves death or signs of adverse side effects such as induction of myocardial infarction. Accordingly, PTCA is accepted as an excellent therapy. However, about 30-40% of the cases that undergo PTCA revert to restenosis at the same site, and if restenosis occurs, PTCA must be performed again, or alternatively, an aorta bypass-forming operation must be performed. This constitutes the most significant problem in the clinical field. Autopsy of cases in which death was caused by reblockage after PTCA revealed that intimal hypertrophy had occurred at the site at which the vascular cavity had been dilated, thus reblocking the site [see, for example, British Heart Journal, 58, 635-643 (1987), Human Pathology, 477-485 (1989)].
Therefore, it is considered that inhibition of intimal hypertrophy would be effective for the prevention of restenosis after PTCA and further for the treatment of arteriosclerosis.
The pharmaceuticals that were expected to open the way up to the remedy of the aforementioned diseases have been studied in both preclinical and clinical stages [American Heart Journal, 122, 171-187 (1991)]. The candidate pharmaceuticals were anticoagulants such as heparin; platelet aggregation inhibitors such as aspirin, dipyridamole, ticlopidine, prostacycline, and their derivatives; thromboxane A2 inhibitors such as trapidil; cell proliferation inhibitors such as ketanserin; calcium antagonists such as diltiazem and nifedipine; lipid decreasing agents such as fish oil, eicosapentaenoic acid and lovastatin; and anti-inflammatory agents such as steroids. However, after actual investigation in clinical situations, none of these drugs were found to have clear utility.
Tranilast is an intimal hypertrophy inhibitor considered to be developed to the most advanced level (Japanese Patent Application Laid-Open (kokai) No. 6-135829). However, due to its weak activity, this drug is not a satisfactory intimal hypertrophy inhibitor.
Thus, presently there are no effective drugs against intimal hypertrophy, and therefore, clinically useful pharmaceuticals are strongly called for.
The active ingredients of the present invention, oxindole derivatives, partially comprise known compounds. The known compounds include synthesis intermediates disclosed in Japanese Patent Publication (kokoku) No. 43-3195, Hungarian Patent Application Laid-Open No. 65452, U.S. Pat. No. 4,002,749, Chem. Ber. 91, 2095 and 91, 1898 (1958), and U.S. Pat. No. 3,413,299; UV absorbers disclosed in U.S. Pat. No. 3,428,649; antidepressant agents or tranquilizers disclosed in Japanese Patent Application Laid-Open (kokai) No. 47-8628; antinootropic agents disclosed in WO 91/01306; drugs for the treatment of central nervous diseases or stomach ulcers disclosed in WO 92/07830; and drugs for the treatment of asthma, rheumatic arthritis, and allergic rhinitis disclosed in WO 95/14667. In addition, myocardial infarction augmenting effect of these compounds is disclosed in European Journal of Medicinal Chemistry, 25(2), 187 (1990), ibid. 27(2), 167 (1992), and ibid. 28, 653 (1993). However, these compounds have not yet been known to serve as intimal hypertrophy inhibitors. Also, analogs of the active ingredients of the present invention, i.e., analogs of the oxindole derivatives, are disclosed in Japanese Patent Application Laid-Open (kokai) Nos. 62-29570, 6-501494, and 7-108900, among which Japanese Patent Application Laid-Open (kokai) Nos. 62-29570 and 6-501494 disclose tyrosine kinase inhibitory activity and Japanese Patent Application Laid-Open (kokai) No. 7-108900 discloses antioxidative action. However, intimal hypertrophy inhibitory action is not at all described in those publications.
Accordingly, the object of the present invention is to provide an excellent intimal hypertrophy inhibiting agent.